1,3,4-Oxadiazole derivatives and process for producing the same

ABSTRACT

Oxadiazole derivatives represented by formula (I):  
                 
 
     (wherein R 1  represents a hydrogen atom or an amino-protective group; R 2 , R 3 , and R 4  each independently represents an alkyl group, a cycloalkyl group, a phenyl group which may be substituted, or a 3,4-methylenedioxyphenyl group, or R 3  and R 4  are taken together to represent a C 2-6  alkylene group), a process of producing the same, and a process for producing oxadiazole derivatives represented by formula (II):  
                 
 
     (wherein all symbols have the same meanings as described above) using the above derivative.  
     According to the invention, the compound represented by formula (II) is produced through fewer steps in a high yield.

TECHNICAL FIELD

[0001] The invention relates to oxadiazole derivatives useful asintermediates for producing pharmaceuticals, a process for producing thesame, and a process for producing 1,3,4-oxadiazole derivatives by usingthe intermediate.

[0002] More specifically, the invention relates to

[0003] (1) a compound represented by formula (I):

[0004] (wherein all symbols have the same meanings as described below),a non-toxic salt thereof, and a hydrate thereof;

[0005] (2) a process for producing the same, and

[0006] (3) a process for producing a compound represented by formula(II):

[0007] (wherein all symbols have the same meanings as described below),comprising using the same.

BACKGROUND ART

[0008] WO9824806 discloses that a compound represented by formula (W-a):

[0009] a compound represented by formula (W-b):

[0010] and a compound represented by formula (W-c):

[0011] (wherein X^(w) and Y^(w) independently represent an oxygen atom,a sulfur atom or a nitrogen atom which may be substituted; R^(1w)represents various substituents, such as an alkyl group which may besubstituted, a hydroxyl group, and an amino group; R^(2w) and R^(3w)independently represent a hydrogen atom or various substituents, such asan alkyl group which may be substituted; A^(w) represents a single bond,a —CO— group, an —NHCO— group, an —SO₂— group, or the like; R^(4w)represents a hydrogen atom or various substituents, such as an alkylgroup which may be substituted; B^(w) represents an —SO₂— group, a —CO—group, or the like; and R^(11w), R^(12w), and E^(w) are taken togetherto form a ring, with the proviso that these definitions are abstractsfrom the disclosure are useful as a serine protease (especially anelastase) inhibitor.

[0012] Upon reviewing the specification in detail, it discloses acompound represented by formula (W-c-1):

[0013] (wherein R^(1w) has the same meaning as described above) amongthe compounds represented by general formula (W-c).

[0014] In the specification, various inhibitors are prepared using, as akey intermediate, a compound represented by formula (W-1):

[0015] (wherein R^(1w) has the same meaning as described above).According to the specification, the compound represented by formula(W-1) is produced in accordance with reaction scheme 1 or 2 shown below.

[0016] In reaction scheme 1, “Cbz” stands for a benzyloxycarbonyl group;“Py”, pyridine; “TEA”, triethylamine; “DMSO”, dimethyl sulfoxide;“Ac₂O”, acetic anhydride; “EDC”,1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride; “HOBt”,1-hydroxybenzotriazole; “DMF”, dimethylformamide; “NMM”,N-methylmorpholine; “Ts”, a tosyl group; “TFA”, trifluoroacetic acid;“Me”, a methyl group; and “Et”, an ethyl group.

[0017] In reaction scheme 2, “Boc” stands for a t-butoxycarbonyl group;“iBu”, an isobutyl group; “DIBAL”, diisobutylaluminum hydride; and“n-BuLi”, n-butyl lithium. Other symbols have the same meanings asdescribed above.

[0018] The specification also discloses that the compound represented byformula (W-c-1) among the compounds represented by formula (W-c) isproduced using the compound represented by formula (W-1) in accordancewith reaction scheme 3 shown below.

[0019] In reaction scheme 3, “T^(2w)” represents a hydrogen atom or abenzyloxycarbonylamino group, and other symbols are as defined above.The oxidation using the Dess-Martin reagent and the Swern oxidation areknown oxidations.

[0020] The process according to reaction scheme 1 involves a number ofsteps (10 steps) for producing the compound represented by formula (W-1)so that it is insufficient in efficiency.

[0021] The present inventors have conducted extensive studies seeking anefficient process for producing the compounds represented by formula(W-c-1) that are promising as pharmaceuticals. As a result, they havefound a process for producing the compound represented by formula (II)shown in reaction scheme 4, in which novel compounds represented byformulae (I-1) and (I-2), namely, the compounds represented by formula(I) are used as a key intermediate.

[0022] In reaction scheme 4, R², R³ and R⁴ each independentlyrepresents:

[0023] (1) a C₁₋₈ alkyl group,

[0024] (2) a C₃₋₇ cycloalkyl group,

[0025] (3) a phenyl group,

[0026] (4) a phenyl group substituted with one to three of a C₁ alkylgroup, a C₁₋₈ alkoxy group, a halogen atom, a trifluoromethyl group, anda trifluoromethoxy group, or

[0027] (5) a 3,4-methylenedioxyphenyl group; or

[0028] (6) R³ and R⁴ are taken together to represent a C₂₋₆ alkylenegroup; and

[0029] R⁵ and R⁶ each independently represents an amino-protectivegroup.

[0030] The inventors have experimented the conventional processes shownin reaction schemes 2 and 3 to find that the overall synthesis yield ofa compound represented by formula (II) in which R², R³ and R⁴ allrepresent a methyl group was 18% through six steps (see ComparativeExamples described below, in which a compound represented by formula(W-XI) was used as a starting material.). In the Comparative Examples,the Swern oxidation was used as an oxidation to produce a compoundrepresented by formula (W-XVII).

[0031] According to the process of the invention shown in reactionscheme 4, on the other hand, the overall synthesis yield of a compoundrepresented by formula (II) wherein R^(1w) is a t-butyl group was 65%through four steps (see Examples described below). In the Examples, at-butoxycarbonyl group was used as an amino-protective group R⁵ in thecompound represented by formulae (V) and the compound represented byformula (I-2), and a benzyloxycarbonyl group was used as anamino-protective group R⁶ in the compound represented by formula (IV)and the compound represented by formula (III).

[0032] Hence, the process of the invention makes it possible to obtainthe compound represented by formula (II) through fewer steps in a higheryield. In other words, the process of the invention provides a desiredcompound through steps less by two in a three- to four-fold yield.

[0033] The present inventors have found that the compound represented byformula (II) can be prepared efficiently by the process represented byreaction scheme 4 which uses the novel compounds represented by formula(I) and thus completed the present invention.

DISCLOSURE OF THE INVENTION

[0034] The present invention relates to

[0035] 1) a compound represented by general formula (I):

[0036] (wherein R¹ represents a hydrogen atom or an amino-protectivegroup; R², R³ and R⁴ each independently represents

[0037] (1) a C₁₋₈ alkyl group,

[0038] (2) a C₃₋₇ cycloalkyl group,

[0039] (3) a phenyl group,

[0040] (4) a phenyl group substituted with one to three of a C₁₋₈ alkylgroup, a C₁₋₈ alkoxy group, a halogen atom, a trifluoromethyl group, anda trifluoromethoxy group, or

[0041] (5) a 3,4-methylenedioxyphenyl group; or

[0042] (6) R³ and R⁴ are taken together to represent a C₂₋₆ alkylenegroup), a non-toxic salt thereof, and a hydrate thereof,

[0043] 2) a process for producing the compound represented by formula(I), and

[0044] 3) a process for producing a compound represented by formula(II):

[0045] (wherein all symbols have the same meanings as described above),comprising using the compound represented by formula (I).

[0046] The term “C₁₋₈ alkyl group” as used herein means a methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl or octyl group or an isomerthereof.

[0047] The term “C₃₋₇ cycloalkyl group” as used herein means acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

[0048] The term “C₁₋₈ alkoxy group” as used herein means a methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxygroup or an isomer thereof.

[0049] The term “halogen atom” as used herein means fluorine, chlorine,bromine or iodine.

[0050] The term “C₂₋₆ alkylene group” as used herein means an ethylene,trimethylene, tetramethylene, pentamethylene or hexamethylene group.

[0051] The amino-protective group represented by R¹, R⁵ or R⁶ in theinvention includes a benzyloxycarbonyl group, a t-butoxycarbonyl group,a trifluoroacetyl group and the like, but is not limited thereto, solong as it is a group which is easily and selectively removable. Forexample, those described in T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, New York (1991) are useful.

[0052] The amino-protective group represented by R¹ and R⁵ is preferablya t-butoxycarbonyl group or a benzyloxycarbonyl group, and morepreferably a t-butoxycarbonyl group.

[0053] The amino-protective group represented by R⁶ is preferably abenzyloxycarbonyl group.

[0054] In the present invention, the group represented by

[0055] is preferably a group in which R², R³ and R⁴ each represents aC₁₋₈ alkyl group; a group in which R² represents a phenyl group, and R³and R⁴ each represents a C₁₋₈ alkyl group; a group in which R²represents a 3,4-methylenedioxyphenyl group, and R³ and R⁴ eachrepresents a C₁₋₈ alkyl group; and a group in which R² represents a C₁₋₈alkyl group, and R³ and R⁴ are taken together to represent a C₂₋₆alkylene group;

[0056] more preferably a group in which R², R³, and R⁴ each represents aC₁₋₄ alkyl group; a group in which R² represents a phenyl group, and R³and R⁴ each represents a C₁₋₄ alkyl group; a group in which R²represents a 3,4-methylenedioxyphenyl group, and R³ and R⁴ eachrepresents a C₁₋₄ alkyl group; and a group in which R² represents a C₁₋₄alkyl group, and R³ and R⁴ are taken together to represent a C₂₋₅alkylene group, and

[0057] most preferably, the group

[0058] represents an α,α-dimethyl-3,4-methylenedioxybenzyl group, at-butyl group, an α,α-dimethylbenzyl group or a 1-methylcyclopropylgroup.

[0059] In the invention, as is apparent to one skilled in the art, themark

shows that the bond is in front of paper (at the β-position) unlessotherwise indicated; the mark

indicates that the bond is on the other side of paper (at theα-position) unless otherwise indicated; the mark

shows that the compound has the bond at the β-position or the α-positionor the compound is a mixture of these compounds; and the mark

indicates that the compound is a mixture of a compound having the bondat the β-position and a compound having the bond at the α-position.

[0060] In the invention, all conceivable isomers are included in thescope thereof unless otherwise indicated. For example, an alkyl group,an alkoxy group and an alkylene group include straight-chain groups andbranched groups. Isomers caused by the presence of an asymmetric carbon(e.g., R or S-forms, α- or βforms, enantiomers, and diastereomers) andoptically active compounds having optical rotation (i.e., D-, L-, d- orI-forms) are all included within the scope of the invention.

PROCESS OF PRODUCING THE COMPOUND OF INVENTION

[0061] The compound represented by formula (I) can be produced byprocesses (1) and (2) described below, the processes according toExamples described below, or known processes.

[0062] (1) Among the compounds represented by formula (I), a compound inwhich R¹ represents an amino-protective group, i.e., a compoundrepresented by formula (I-2):

[0063] (wherein all symbols have the same meanings as described above)is prepared by reacting a compound represented by formula (V):

[0064] (wherein R⁵ has the same meaning as described above) and acompound represented by formula (VI):

[0065] (wherein all symbols have the same meanings as described above).

[0066] The reaction between the compound represented by formula (V) andthe compound represented by formula (VI) is carried out in an inertorganic solvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran, toluene, dimethylformamide, or the like) in thepresence of a base (e.g., lithium diisopropylamide (LDA), or the like)and a tertiary amine (e.g., tetramethylethylenediamine, or the like) at−78 to 0° C.

[0067] (2) Among the compounds represented by formula (I), a compound inwhich R¹ is a hydrogen atom, i.e., a compound represented by formula(I-1):

[0068] (wherein all symbols have the same meanings as described above)is prepared by subjecting the compound represented by formula (I-2) to adeprotection reaction of the amino-protecting group.

[0069] The deprotection reaction for the amino-protecting groupincludes, for example,

[0070] 1) a deprotection reaction under alkaline conditions,

[0071] 2) a deprotection reaction under acidic conditions, and

[0072] 3) a deprotection reaction by hydrolysis.

[0073] More specifically,

[0074] 1) the deprotection reaction under alkaline conditions is carriedout, for example, at 0° C. to 40° C. in an organic solvent (e.g.,methanol, tetrahydrofuran, dioxane, dimethylformamide, or the like)using an alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, or the like), an alkaline earth metalhydroxide (e.g., barium hydroxide, calcium hydroxide, or the like), anorganic amine (e.g., triethylamine, N-methylmorpholine,diisopropylethylamine, piperidine, or the like) or a quaternary ammoniumsalt (e.g., tetrabutylammonium fluoride, or the like) an aqueoussolution thereof or a mixture thereof.

[0075] 2) The deprotection reaction under acidic conditions is carriedout, for example, at 0° C. to 100° C. in an organic solvent (e.g.,methylene chloride, chloroform, dioxane, ethyl acetate, anisole, or thelike) or without a solvent using an organic acid (e.g., acetic acid,trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide, orthe like) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid,or the like), or a mixture thereof (e.g., hydrogen bromide/acetic acid,or the like).

[0076] 3) The deprotection reaction by hydrolysis is carried out, forexample, in an inert solvent (e.g., ethers (tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol,etc.), benzene solvents (benzene, toluene, etc.), ketones (acetone,methyl ethyl ketone, etc.), nitrites (acetonitrile, etc.), amides(dimethylformamide, etc.), water, ethyl acetate, acetic acid, or mixedsolvent of two or more thereof) in the presence of a hydrogenationcatalyst (e.g., palladium-carbon, palladium black, palladium, palladiumhydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride,or the like) and in the presence or absence of an inorganic acid (e.g.,hydrochloric acid, sulfuric acid, hypochloric acid, boric acid,tetrafluoroboric acid, or the like) or an organic acid (e.g., aceticacid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formicacid, or the like) in a hydrogen atmosphere either under normal pressureor under pressure or in the presence of ammonium formate at a 0° C. to200° C. In using an acid, the acid may be used in the form of its salt.

[0077] As is easily understood by one skilled in the art, the desiredcompound of the invention can be easily obtained by a proper choice ofthese reactions.

[0078] The deprotection reaction of the compound represented by formula(I-2) is preferably carried out by the reaction under acidic conditionsor the reaction by hydrolysis. The reaction under acidic conditions ismore preferred.

[0079] The compound represented by formula (I-1) is allowed to reactwith the compound represented by formula (IV):

[0080] (wherein R⁶ has the same meaning as described above) to producethe compound represented by formula (III):

[0081] (wherein all symbols have the same meanings as described above).The reaction for producing the compound represented by formula (III) isan amidation.

[0082] The amidation is known in the art. It includes, for example,

[0083] 1) a process using an acid halide,

[0084] 2) a process using a mixed acid anhydride, and

[0085] 3) a process using a condensing agent.

[0086] More specifically,

[0087] 1) the process using an acid halide is carried out by, forexample, reacting the compound represented by formula (IV) with an acidhalide (e.g., oxalyl chloride thionyl chloride, or the like) in an inertorganic solvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran, or the like) or without a solvent at −20° C. to arefluxing temperature and reacting the resulting acid halide with thecompound represented by formula (I-1) in an inert organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran, or thelike) in the presence of a tertiary amine (e.g., pyridine,triethylamine, dimethylaniline, dimethylaminopyridine, or the like) at−20° C. to 40° C.

[0088] 2) The process using a mixed acid anhydride is carried out by,for example, reacting the compound represented by formula (IV) with anacid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl chloride, orthe like) or an acid derivative (e.g., ethyl chloroformate (ethylchlorocarbonate), isobutyl chloroformate (isobutyl chlorocarbonate), orthe like) in an inert organic solvent (e.g., chloroform, methylenechloride, diethyl ether, tetrahydrofuran, or the like) or without asolvent in the presence of a tertiary amine (e.g., pyridine,triethylamine, dimethylaniline, dimethylaminopyridine,N-methylmorpholine, or the like) at −20° C. to 40° C. and reacting theresulting mixed acid anhydride with the compound represented by formula(I-1) in an inert organic solvent (e.g., chloroform, methylene chloride,diethyl ether, tetrahydrofuran, or the like) at −20° C. to 40° C.

[0089] 3) The process using a condensing agent is conducted by, forexample, reacting the compound represented by formula (IV) with thecompound represented by formula (I-1) in an organic solvent (e.g.,chloroform, methylene chloride, dimethylformamide, diethyl ether,tetrahydrofuran, or the like) or without a solvent in the presence orabsence of a tertiary amine (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, or the like) using a condensingagent (e.g., 1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, orthe like) and with or without 1-hydroxybenztriazole (HOBt) at 0° C. to40° C.

[0090] The reactions 1), 2) and 3) are preferably carried out in anatmosphere of an inert gas (e.g., argon, nitrogen, or the like) underanhydrous conditions.

[0091] The amidation between the compound represented by formula (I-1)and the compound represented by formula (IV) is preferably carried outby the process using a mixed acid anhydride.

[0092] The reaction for converting the compound represented by formula(III) into the compound represented by formula (II) can be carried outby the above deprotection reaction of the amino-protecting group.

[0093] The deprotection reaction of the amino-protecting group forconverting the compound represented by formula (III) into the compoundrepresented by formula (II) is preferably carried out by hydrolysis.

[0094] The compound represented by formula (V) and the compoundrepresented by formula (VI) are produced by the process described inWO9824806 or Examples described below.

[0095] The compound represented by formula (IV) is produced by theprocess described in EP 528633 (JP-A-5-286946).

[0096] The other starting materials and reagents used in the presentinvention are known per se or can be prepared by known processes.

[0097] As is easily understood by one skilled in the art, the compoundsrepresented by formulas (I-2), (I-1), (III) and (II) in their opticallyactive form can be easily produced using an optically active compound asthe compound represented by formula (V).

[0098] For example, among the compounds represented by formula (V),t-butylN-((1R)-1-(N′-methyl-N′-methoxyaminocarbonyl)-2-methylpropyl)carbamate(CAS Registry No. 190260-92-5), t-butylN-((1S)-1-(N′-methyl-N′-methoxyaminocarbonyl)-2-methylpropyl)carbamate(CAS Registry No. 160711-20-6), benzylN-((1S)-1-(N′-methyl-N′-methoxyaminocarbonyl)-2-methylpropyl)carbamate(CAS Registry No. 114744-84-2), and the like are known. Use of theseoptically active compounds easily provides, for example,N-((1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,and the like among the compounds represented by formula (III); andN-((1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide,and the like among the compounds represented by formula (II).

[0099] The product of each reaction in the invention is purified throughcommon purification means, for example, distillation under normalpressure or reduced pressure, high performance liquid chromatographyusing silica gel or magnesium silicate, thin layer chromatography,column chromatography, washing, recrystallization, and the like. Thepurification may be carried out at each reaction or after completion ofseveral reactions.

[0100] The compound represented by general formula (I) can be convertedinto a salt by a known method. The salt is preferably non-toxic andwater-soluble. Examples of suitable salts include salts with alkalimetals (e.g., potassium, sodium, and the like), salts with alkalineearth metals (e.g., calcium, magnesium, and the like), ammonium salts,and pharmaceutically acceptable salts with organic amines (e.g.,tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane,lysine, arginine, N-methyl-D-glucamine, and the like).

[0101] The compound represented by formula (I) according to the presentinvention can be converted into an acid addition salt by a knownprocess. The acid addition salt is preferably non-toxic andwater-soluble. Examples of suitable acid addition salts includeinorganic acid salts, such as hydrochlorides, hydrobromides, sulfates,phosphates, nitrates, and the like; and organic acid salts, such asacetates, trifluoroacetates, lactates, tartrates, oxalates, fumarates,maleates, citrates, benzoates, methanesulfonates, ethanesulfonates,benzenesulfonates, toluenesulfonates, isethionates, glucuronates,gluconates, and the like.

[0102] The compound represented by formula (I) according to theinvention or a non-toxic salt thereof can be converted into a hydratethereof by a known method.

INDUSTRIAL APPLICABILITY

[0103] The process of the invention provides the compound represented byformula (II) through a fewer steps using the novel intermediaterepresented by formula (I) and is therefore useful as an efficientindustrial process of production.

BEST MODE FOR CARRYING OUT THE INVENTION

[0104] The present invention will now be illustrated in greater detailby way of Reference Examples, Examples, and Comparative Examples, butthe invention is not limited thereto.

[0105] Solvents in parentheses shown in the part of chromatographicseparation and TLC are eluents or developing solvents used, and ratiosare by volume.

[0106] Solvents in parentheses shown in the part of NMR are solventsused for the measurement.

Reference Example 1 Synthesis of t-butylN-(1-(N′-methyl-N′-methoxyaminocarbonyl)-2-methylpropyl)carbamate

[0107]

[0108] N,O-Dimethylhydroxylamine hydrochloride (3.37 kg) and1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (5.73 kg) were dissolvedin pyridine (19 liters (L)) at room temperature in a nitrogenatmosphere, and 2-t-butoxycarbonylamino-3-methylbutanoic acid (5.00 kg)was added thereto at 5° C. or lower, followed by stirring at 20-30° C.for 2 hours. Ice-water (23.8 L) and toluene (15.8 L) were added to thereaction mixture, and the resulting layers were separated. The aqueouslayer was extracted with a mixed solvent (toluene:ethyl acetate=1:1,15.8 L). The organic layers were combined and washed with 1 Nhydrochloric acid (40 L, twice). Ethyl acetate (7.9 L) was added to theorganic layer, and the mixture was washed with a saturated aqueoussolution of sodium hydrogencarbonate (16 L, twice), water (30 L, twice),and saturated saline (16 L, twice) successively, followed byconcentration. The residue was dissolved in methanol (12 L) at 40° C.,and water (30 L) was added thereto to precipitate a solid, followed bystirring at 25° C. for 2 hours and then at 5° C. or lower for 2 at leasthours. The precipitated solid was filtrated and washed with water (5 L).The solid was dried in vacuo at 30° C. for at least 15 hours to obtainthe title compound (5.16 kg; yield: 86%) having the following physicalproperties.

[0109] TLC: Rf 0.49 (hexane:ethyl acetate=2:1)

[0110] NMR (CDCl₃): δ5.13 (brd, 1H), 4.57 (brt, 1H), 3.77 (s, 3H), 3.22(s, 3H), 1.97 (m, 1H), 1.44 (s, 9H), 0.96 (d, J=6.8 Hz, 3H), 0.91 (d,J=6.8 Hz, 3H).

Reference Example 2 Synthesis of Pivaloylhydrazine

[0111]

[0112] Methyl pivalate (1040 ml) and hydrazine monohydrate (760 ml) wereheated under reflux for 14.5 hours in an argon stream. The reactionmixture was cooled to room temperature and concentrated. The residue wascooled with ice, and the precipitated crystals were collected byfiltration. The filtered material was washed with hexane (250 ml, twice;and 300 ml, once) to obtain the title compound. Furthermore, the motherliquid (510 g) was cooled with ice, and the precipitated crystals werecollected by filtration. The filtered material was washed with hexane(100 ml, twice; and 200 ml, once) to obtain the title compound havingthe following physical properties (total yield: 571.8 g, 63%).

[0113] TLC: Rf 0.59 (chloroform:methanol=10:1)

[0114] NMR (CDCl₃): δ7.06 (brs, 1H), 3.87 (brs, 2H), 1.21 (s, 9H)

Reference Exmaple 3 Synthesis of 2-t-butyl-1,3,4-oxadiazole

[0115]

[0116] A mixture of the compound produced in Reference Example 2 (570g), methyl orthoformate (805 ml) and p-toluenesulfonic acid monohydrate(14.0 g) was heated under stirring for 9 hours while distilling offproduced methanol. The reaction mixture was cooled to room temperatureand distilled under reduced pressure to obtain a compound of theinvention (538.4 g; 86%) having the following physical properties.

[0117] TLC: Rf 0.68 (chloroform:methanol=10:1)

[0118] NMR (CDCl₃): δ8.33 (s, 1H), 1.45 (s, 9H)

Reference Exmalpe 4 Synthesis ofN-hydroxy-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxamide

[0119]

[0120] Triethylamine (49.4 ml) was added to a solution of1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxylicacid (97.3 g) in tetrahydrofuran (800 ml) in an ice bath in an argonatmosphere, and isobutyl chlorocarbonate (45.6 ml) was added dropwisethereto at 5° C. or lower, followed by stirring at the same temperaturefor 1 hour. To the reaction mixture was added a 50% hydroxylamineaqueous solution (422 ml), followed by stirring for 20 minutes. Thereaction mixture was separated to layers. The aqueous layer wasextracted with ethyl acetate (200 ml). The organic layers were combined,washed with saturated saline (200 ml), and concentrated. To the residuewas added toluene (200 ml), followed by concentration. The resultingcrude crystals were washed with isopropyl ether (1000 ml) by heatingunder reflux for 10 minutes, cooled to room temperature, and crystalswere collected by filtration. The collected crystals were dried in vacuoat room temperature overnight to obtain the title compound (93.3 g;yield: 91%) having the following physical properties.

[0121] TLC: RF 0.5 (ethyl acetate);

[0122] NMR (CDCl₃): δ8.95 (s, 1H), 7.62-7.45 (m, 5H), 4.76 (t, J=5.8 Hz,1H), 4.21 (2H, d, J=5.8 Hz), 3.30 (6H, s).

Reference Example 5 Synthesis ofN-acetyloxy-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxamide

[0123]

[0124] Pyridine (5.66 ml) was added to a suspension of the compoundproduced in Reference Example 4 (15.95 g) in tetrahydrofuran (50 ml) atroom temperature in an argon atmosphere, and acetic anhydride (5.19 ml)was added dropwise thereto, followed by stirring for 20 minutes. Ethylacetate (150 ml) and 1N hydrochloric acid (84 ml) were added to thereaction mixture, and the resulting layers were separated. The organiclayer was washed with an aqueous sodium chloride solution (saturatedsaline (50 ml) and water (50 ml)) and a mixed solution (saturated saline(50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50ml)) successively, followed by concentration to obtain the titlecompound (16.9 g; crude product) having the following physicalproperties.

[0125] TLC: Rf 0.44 (toluene:acetone=4:1)

[0126] NMR (CDCl₃): δ8.99 (s, 1H), 7.62-7.45 (m, 5H), 4.79 (t, J=5.4 Hz,1H), 4.22 (d, J=5.4 Hz, 2H), 3.30 (s, 6H), 2.30 (s, 3H).

Reference Example 6 Synthesis of5-amino-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine

[0127]

[0128] A suspension of the compound produced in Reference Example 5(16.9 g) in tetrahydrofuran (200 ml) was heated to obtain a solution.Water (18 ml) was added thereto at 40° C., and1,8-diazabicyclo[5.4.0]-7-undecene (9.35 ml) was added thereto at 50°C., followed by heating under reflux for 1 hour. After cooling thereaction mixture to room temperature, toluene (100 ml) and a saturatedaqueous solution of ammonium chloride (100 ml) were added thereto, andthe resulting layers were separated. The organic layer was washed with asaturated aqueous ammonium chloride solution and saturated saline (100ml) successively and concentrated to obtain the title compound (15.7 g;crude product) having the following physical properties.

[0129] TLC: Rf 0.26 (toluene:acetone=4:1)

[0130] NMR (CDCl₃): δ7.55-7.38 (m, 6H), 4.77 (t, J=5.6 Hz, 1H), 4.14 (d,J=5.6 Hz, 2H), 4.02 (brs, 2H), 3.27 (s, 6H)

Reference Example 7 Synthesis of5-benzyloxycarbonylamino-1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine

[0131]

[0132] A mixture of the compound produced in Reference Example 6 (15.7g), tetrahydrofuran (75 ml), water (75 ml), and sodium hydrogencarbonate(5.88 g) was cooled with ice, and benzyloxycarbonyl chloride (8.56 ml)was added dropwise thereto at 5° C. or lower, followed by stirring at 5°C. overnight. Ethyl acetate (100 ml) was added to the reaction mixture,and the resulting layers were separated. The organic layer was washedwith saturated saline (100 ml), followed by concentration to obtain thetitle compound (22.0 g; crude product) having the following physicalproperties.

[0133] TLC: Rf 0.67 (toluene:acetone=4:1)

[0134] NMR (CDCl₃): δ8.73 (brs, 1H), 7.60-7.30 (m, 10H), 5.24 (s, 2H),4.71 (t, J=5.5 Hz, 1H), 4.15 (d, J=5.5 Hz, 2H), 3.26 (s, 6H)

Reference Example 8 Synthesis of5-benzyloxycarbonylamino-1-formylmethyl-6-oxo-2-phenyl-1,6-dihydropyrimidine

[0135]

[0136] A mixture of the compound produced in Reference Example 7 (22.0g), 1N hydrochloric acid (10 ml), and acetic acid (30 ml) was heated to70-77° C., followed by stirring for 2 hours. The reaction mixture wascooled to room temperature, water (75 ml) and a mixed solvent(toluene:ethyl acetate=4:1, 60 ml) were added thereto, and the resultinglayers were separated. The aqueous layer was extracted with a mixedsolvent (toluene:ethyl acetate=4:1, two 30 ml portions). The organiclayers were combined and washed with water (50 ml), a saturated aqueoussolution of sodium hydrogencarbonate (50 ml), and saturated saline (50ml) successively, and dried over anhydrous magnesium sulfate, followedby concentration to obtain the title compound (16.8 g; crude product)having the following physical properties.

[0137] TLC: Rf 0.36 (hexane:ethyl acetate=1:1)

[0138] NMR (CDCl₃): δ9.59 (s, 1H), 8.79 (brs, 1H), 7.60-7.10 (m, 10H),5.24 (s, 2H), 4.77 (s, 2H)

Reference Example 9 Synthesis of5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-ylmethylcarboxylicAcid

[0139]

[0140] An aqueous solution (20 ml) of sodium dihydrogenphosphate (7.20g) was added to a solution of the compound produced in Reference Example8 (16.8 g) in a mixed solvent (t-butanol:water=4:1, 100 ml), followed bycooling with ice. To the reaction mixture was added 2-methyl-2-butene(23.8 ml), and an aqueous solution (32 ml) of sodium chlorite (19.78 g)was added dropwise thereto, followed by stirring at room temperature for3 hours. Ethyl acetate (30 ml) was added to the reaction mixture, andthe resulting layers were separated. To the organic layer were added asaturated aqueous sodium chloride solution (60 ml) and ethyl acetate (30ml), and the resulting layers were separated. The organic layer waswashed with a 10% aqueous solution of sodium hydrogensulfite (60 ml).The aqueous layer was extracted with ethyl acetate (50 ml). The organiclayers were combined and washed with 1N hydrochloric acid (60 ml) andsaturated saline (60 ml) successively, and dried over anhydrousmagnesium sulfate, followed by concentration. Ethyl acetate (50 ml) wasadded to the residue, followed by concentration. Ethyl acetate (50 ml)was further added to the residue, followed by concentration. To theresulting crude crystals was added ethyl acetate (35 ml), followed byheating under reflux for 15 minutes. Isopropyl ether (17.5 ml) wasadded, followed by heating under reflux for further 15 minutes. Thesolution was cooled to room temperature, followed by stirring at 5° C.overnight. The precipitated crystals were collected by filtration, andwashed with isopropyl ether (50 ml). The crystals were dried in vacuo toobtain the compound of the invention (11.99 g; yield: 63%) having thefollowing physical properties.

[0141] TLC: Rf 0.55 (chloroform:methanol:acetic acid=18:1:1)

[0142] NMR (CD₃OD): δ8.65 (s, 1H), 7.60-7.25 (m, 10H), 5.23 (s, 2H),4.60 (s, 2H)

EXAMPLE 1 Synthesis of t-butylN-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)carbamate

[0143]

[0144] A 2.0 M solution of lithium diiospropylamide (19.65 kg) was addeddropwise to a solution of the compound produced in Reference Example 1(2.52 kg), the compound produced in Reference Example 3 (6.10 kg), andtetramethylethylenediamine (5.62 kg) in tetrahydrofuran (25.2 L) at −65°C. or less in an argon stream, followed by stirring at −25° C. to −20°C. for 3 to 5 hours. The reaction mixture was poured into a cool 10%aqueous citric acid solution (93 L) and extracted with ethyl acetate. Tothe organic layer was added 1N hydrochloric acid (96.8 L), followed bystirring for 1 hour, and the resulting layers were separated. Theorganic layer was washed with a 5% aqueous potassium carbonate solution(50.4 L), water (25.2 L, twice), and saturated saline (8.4 L)successively, and dried over anhydrous magnesium sulfate. The anhydrousmagnesium sulfate was separated by filtration and washed withtetrahydrofuran (2.8 L). The organic layer was concentrated to obtainthe compound of the invention (3.69 kg, crude product) having thefollowing physical properties.

[0145] TLC: Rf 0.70 (hexane:ethyl acetate=2:1)

[0146] NMR (CDCl₃): δ5.30-5.05 (m, 2H), 2.46 (m, 1H), 1.48 (s, 9H), 1.43(s, 9H), 1.09 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

EXAMPLE 1(1) Synthesis of t-butylN-((2S)-1-(2-α,α-dimethylbenzyl)-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)carbamate

[0147]

[0148] The compound of the invention having the following physicalproperties was obtained in the same manner as in Example 1, except forreplacing the compound produced in Reference Example 3 with acorresponding oxadiazole derivative and replacing the compound producedin Reference Example 1 with t-butylN-((2S)-1-(N′-methyl-N′-methoxyaminocarbonyl)-2-methylpropyl)carbamate.

[0149] TLC: Rf 0.50 (ethyl acetate:n-hexane=1:2)

[0150] NMR (CDCl₃): δ7.32 (m, 5H), 5.16 (m, 2H), 2.45 (m, 1H), 1.89 (s,6H), 1.43 (s, 9H), 1.07 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=7.2 Hz) clEXAMPLE 2

Synthesis of1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylamineHydrochloride

[0151]

[0152] A solution of the compound produced in Example 1 (3.15 kg) inethyl acetate (4.3 L) was added dropwise to a 4N hydrogen chloride-ethylacetate solution (9.7 L) at 10-20° C. in a nitrogen stream, followed bystirring for 1.5-2 hours. A 4N hydrogen chloride-ethyl acetate solution(4.8 L) was added to the reaction mixture at 10-20° C., followed bystirring for 1 hour. The reaction mixture was concentrated, ethylacetate (8.8 L) was added thereto, followed by concentration. Ethylacetate (8.8 L) was again added to the concentrate, followed byconcentration. t-Butyl methyl ether (29.0 L) was added to theconcentrate, followed by stirring at 5° C. or lower for at least 2hours. The precipitated solid was collected by filtration. The filteredsolid was washed with a mixed solvent (t-butyl methyl ether (3.84 L) andethyl acetate (0.96 L)) and dried in vacuo at 30° C. for at least 15hours to obtain the compound of the invention (2.16 kg; yield throughthe two steps: 86%) having the following physical properties.

[0153] TLC: Rf 0.90 (chloroform:methanol=10:1)

[0154] NMR (CD₃OD): δ5.05 (d, J=3.8 Hz, 1H), 2.85 (m, 1H), 1.48 (s, 9H),1.35 (d, J=6.9 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H)

EXAMPLE 2(1) Synthesis of(2S)-1-(2-(α,α-dimethylbenzyl)-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylaminehydrochloride

[0155]

[0156] The compound of the invention having the following physicalproperties was obtained in the same manner as in Example 2, except forreplacing the compound produced in Example 1 with the compound producedin

EXAMPLE 1(1)

[0157] TLC: Rf 0.50 (chloroform:methanol=10:1)

[0158] NMR (CDCl₃): δ9.05 (brs, 2H), 7.28 (m, 5H), 4.96 (m, 1H), 2.79(m, 1H), 1.87 (s, 6H), 1.29 (d, J=6.8 Hz, 3H), 1.02 (d, J=7.2 Hz, 3H)

EXAMPLE 3 Synthesis ofN-((1RS)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide

[0159]

[0160] N-Methylmorpholine (634 g) was added to a solution of thecompound produced in Reference Example 9 (2.38 kg) in tetrahydrofuran(12.9 L) at −5° C. or lower in an argon stream, ethyl chlorocarbonate(680 g) was added dropwise thereto at −2° C. or lower, and the reactionmixture was stirred at −5° C. or lower for 30 minutes. The compoundproduced in Example 2 (1.64 kg) was added to the reaction mixture at −5°C. or lower, followed by stirring for 30 minutes. To the reactionmixture was added N-methylmorpholine (634 g) at −5° C. or lower,followed by stirring for 30 minutes. t-Butyl methyl ether (24.8 L) and1N hydrochloric acid (12.9 L) were added to the reaction mixture, andthe resulting layers were separated. The organic layer was washed with a5% aqueous sodium hydrogencarbonate solution (12.9 L), a 5% aqueouspotassium carbonate solution (12.9 L), 1N hydrochloric acid (12.9 L),water (12.9 L), and saturated saline (12.9 L) successively, and driedover anhydrous magnesium sulfate. The magnesium sulfate was separated byfiltration and washed with tetrahydrofuran (18 L). The organic layer wasconcentrated to obtain the compound of the invention (3.61 kg; yield:98%) having the following physical properties.

[0161] TLC: Rf 0.33 (hexane:ethyl acetate=1:1)

[0162] NMR (CDCl₃): δ8.78 (s, 1H), 7.60-7.30 (m, 10H), 6.74 (d, J=8.5Hz, 1H), 5.43 (dd, J=8.5, 5.2 Hz, 1H), 5.23 (s, 2H), 4.64 (d, J=15.3 Hz,1H), 4.60 (d, J=15.3 Hz, 1H), 2.50 (m, 1H), 1.47 (s, 9H), 1.06 (d, J=6.8Hz, 3H), 0.87 (d, J=6.8 Hz, 3H).

EXAMPLE 4 Synthesis ofN-((1RS)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide

[0163]

[0164] To a solution of the compound produced in Example 3 (1.61 kg) inmethanol (27 L) was added 10% palladium-carbon (water content: 50%; 274g) at room temperature in an argon atmosphere. Argon substitution wascarried out three times, and then hydrogen substitution was carried outthree times. The reaction mixture was stirred at 25° C. and 3 atm for 25minutes. After argon substitution was carried out three times, thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was dissolved in methanol (54.8 L), followed by filtration.Water (54.8 L) was added to the filtrate, and seed crystals (12.4 g)were added to thereto, followed by stirring overnight and then stirringat 5-10° C. for 1 hour. The precipitated crystals were collected byfiltration, washed with water (30 L), and dried in vacuo at 60° C. forat least 38 hours to obtain the compound of the invention (1.90 kg;yield: 77%) having the following physical properties.

[0165] TLC: Rf 0.45 (methylene chloride:ethyl acetate:ethanol=10:10:1)

[0166] NMR (CDCl₃): δ7.58-7.35 (m, 6H), 6.94 (d, J=8.4 Hz, 1H), 5.44(dd, J=8.4, 4.9 Hz, 1H), 4.66 (d, J=15.4 Hz, 1H), 4.60 (d, J=15.4 Hz,1H), 4.06 (brs, 2H), 2.51 (m, 1H), 1.48 (s, 9H), 1.07 (d, J=6.9 Hz, 3H),0.87 (d, J=6.9 Hz, 1H)

Comparative Examples

[0167] Among the compounds represented by formula (W-c-1), a compound inwhich R^(1w) is a t-butyl group was produced by the processes shown inthe previously described reaction schemes 2 and 3.

Comparative Example 1 Synthesis of t-butylN-(1-formyl-2-methylpropyl)carbamate

[0168]

[0169] Diisobutylaluminum hydride (1.0 M toluene solution, 80 ml) wasadded dropwise to a solution of the compound produced in ReferenceExample 1 (9.0 g) in anhydrous tetrahydrofuran (500 ml) at −78° C. in anargon stream, followed by stirring for 30 minutes. Methanol (100 ml) wasadded to the reaction mixture, the temperature was raised to 0° C., anda saturated aqueous ammonium chloride solution (100 ml) was addedthereto. The reaction mixture was filtered, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=19:1→4:1) to obtain the titlecompound (5.4 g; yield: 78%) having the following physical properties.

[0170] TLC: Rf 0.55 (hexane:ethyl acetate=4:1)

[0171] NMR (CDCl₃): δ9.62 (s, 1H), 5.16 (brs, 1H), 4.25 (brs, 1H), 2.27(m, 1H), 1.43 (s, 9H), 1.03 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H)

Comparative Example 2 Synthesis of t-butylN-(1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymethyl)-2-methylpropyl)carbamate

[0172]

[0173] n-Butyl lithium (1.6 M hexane solution, 308 ml) was addeddropwise to a solution of the compound produced in Reference Example 3(62.1 g) in tetrahydrofuran (1.65 L) at −70° C. in an argon atmosphere,followed by stirring for 40 minutes. Magnesium bromide diethyl etherate(127 g) was added to the reaction mixture, and the temperature wasraised to −45° C., followed by stirring for 1.5 hours. A solution of thecompound prepared in Comparative Example 1 (90.0 g) in tetrahydrofuran(60 ml) was added to the reaction mixture, and the temperature wasraised to −20° C., followed by stirring for 3.5 hours. A saturatedaqueous solution of ammonia chloride (1.5 L) was added to the reactionmixture, followed by extraction with ethyl acetate (1.8 L). The organiclayer was washed with water (1 L, three times) and saturated saline (1L) successively, dried over anhydrous sodium sulfate, and concentrated.The residue was purified by silica gel column chromatography (ethylacetate:hexane=1:20→1:1) to obtain the title compound (76.8 g; yield:53%) having the following physical properties.

[0174] TLC: Rf 0.42 (ethyl acetate:hexane=1:1).

[0175] NMR (CDCl₃): δ5.18-4.90 (m, 2H), 4.51 and 4.12 (each m, totally1H), 3.91 and 3.66 (each m, totally 1H), 1.95 (m, 1H), 1.42, 1.41 and1.34 (each s, totally 18H), 1.15-0.90 (m, 6H).

Comparative Example 3 Synthesis of1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymethyl-2-methylpropylaminehydrochloride

[0176]

[0177] A solution of the compound produced in Comparative Example 2(76.3 g) and a 4N hydrogen chloride-dioxane solution (1 L) in dioxane(200 ml) was vigorously stirred at room temperature for 2 hours,followed by concentration. The residue was solidified with diethyl etherand subjected to azeotropy with benzene to quantitatively obtain thetitle compound (66.1 g) having the following physical properties.

[0178] TLC: Rf 0.30 and 0.26 (methanol:chloroform=1:10)

[0179] NMR (CDCl₃): δ8.34 and 8.24 (each br, each 1H), 5.60 (br, 1H),3.97-3.60 (m, 2H), 2.08 (m, 1H), 1.42 and 1.41 (each s, totally 9H),1.25-0.95 (m, 6H).

Comparative Example 4 Synthesis ofN-(1-(2-t-butyl-1,3,4-oxadiazol-5-yl)hydroxymetyl-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide

[0180]

[0181] To a solution of the compound produced in Reference Example 9(10.0 g) and the compound produced in Comparative Example 3 (8.16 g) inanhydrous dimethylformamide (88 ml) were added 1-hydroxybenzotriazolemonohydrate (4.44 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (6.62 g) in an argon stream under cooling with ice, andN-methylmorpholine (3.19 ml) was added dropwise thereto. The reactionmixture was stirred under ice-cooling for 20 minutes and then at roomtemperature for 6.5 hours, followed by concentration. Ethyl acetate (100ml) and water (100 ml) were added to the residue, and the resultinglayers were separated. The organic layer was washed with a saturatedaqueous solution of ammonium chloride (60 ml, twice), a saturatedaqueous solution of sodium hydrogencarbonate (60 ml, twice), water (60ml), and saturated saline (60 ml) successively, dried over anhydroussodium sulfate, and concentrated. The resulting solid (14.7 g; yield:95%) was used in the subsequent reaction without purification.

[0182] TLC: Rf 0.60 and 0.55 (chloroform:methanol=9:1)

[0183] NMR (CDCl₃): δ8.80 and 8.71 (each brs, total 1H), 7.64-7.24 (m,11H), 7.15 and 6.79 (each brd, J=9.8 Hz, total 1H), 5.28-4.98 (m, ca.1.5H), 5.20 (s, 2H), 4.69 (brs, ca. 0.5H), 4.58 and 4.46 (each brs,total 2H), 4.30 and 4.05 (each m, total 1H), 2.05-1.65 (m, 1H), 1.38 and1.34 (each s, total 9H), 1.08, 0.96, 0.92, and 0.91 (each d, J=6.4 Hz,total 6H).

Comparative Example 5 Synthesis ofN-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide

[0184]

[0185] A solution of dimethyl sulfoxide (7.1 ml) in anhydrous methylenechloride (100 ml) was added dropwise to a solution of oxalyl chloride(4.4 ml) in anhydrous methylene chloride (100 ml) at −60° C. or lower inan argon stream, followed by stirring for 40 minutes. A solution of thecompound produced in Comparative Example 4 (14.7 g) in a mixed solvent(anhydrous methylene chloride (75 ml) and dimethyl sulfoxide (10 ml))was added dropwise to the reaction mixture at −60° C. or lower, followedby stirring for 2 hours. Triethylamine (69.8 ml) was added dropwise tothe reaction mixture at −60° C. or lower, followed by stirring at roomtemperature overnight. The reaction mixture was cooled with ice, and 2Nhydrochloric acid (200 ml) was added dropwise thereto. The organic layerwas washed with 1 N hydrochloric acid (150 ml), water (150 ml), andsaturated saline (150 ml) successively, dried over anhydrous magnesiumsulfate, and concentrated. The resulting solid (14.6 g; yield: 100%) wasused in the subsequent reaction without purification.

Comparative Example 6 Synthesis ofN-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide

[0186]

[0187] A solution of aluminum chloride (20.0 g) in nitromethane (70 ml)was added to a solution of the compound produced in Comparative Example5 (14.4 g) and anisole (16.0 ml) in nitromethane (70 ml) under coolingwith ice, followed by stirring under ice cooling for 10 minutes and thenstirring at room temperature for 14 hours. The reaction mixture waspoured into ice-water (200 ml) and extracted with ethyl acetate (120 mland 40 ml). The organic layer was washed with a sodium chloride aqueoussolution (a saturated sodium chloride aqueous solution (100 ml)+water(100 ml)) and saturated saline (200 ml) successively, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:2→0:1) toobtain a solid (6.7 g). The solid was washed with a mixed solvent(hexane:ethyl acetate=1:3) to obtain the title compound (5.2 g; yield:46%).

1. A compound represented by formula (I):

(wherein R¹ represents a hydrogen atom or an amino-protective group; R²,R³ and R⁴ each independently represents (1) a C₁₋₈ alkyl group, (2) aC₃₋₇ cycloalkyl group, (3) a phenyl group, (4) a phenyl groupsubstituted with one to three of a C₁₋₈ alkyl group, a C₁₋₈ alkoxygroup, a halogen atom, a trifluoromethyl group, and a trifluoromethoxygroup, or (5) a 3,4-methylenedioxyphenyl group; or (6) R³ and R⁴ aretaken together to represent a C₂₋₆ alkylene group), a non-toxic saltthereof or a hydrate thereof.
 2. The compound according to claim 1,wherein R¹ represents a hydrogen atom in formula (I), said compoundbeing represented by formula (I-1):

(wherein R², R³ and R⁴ have the same meanings as in claim 1).
 3. Thecompound according to claim 1, wherein R¹ represents a benzyloxycarbonylgroup, a t-butoxycarbonyl group or a trifluoroacetyl group in formula(I), said compound being represented by formula (I-2):

(wherein R⁵ represents a benzyloxycarbonyl group, a t-butoxycarbonylgroup or a trifluoroacetyl group; and R², R³ and R⁴ have the samemeanings as in claim 1).
 4. The compound according to claim 1, whereinR², R³ and R⁴ each independently represents a C₁₋₈ alkyl group, a phenylgroup or a 3,4-methylenedioxyphenyl group, or R³ and R⁴ are takentogether to represent a C₂₋₅ alkylene group in formula (I).
 5. Thecompound according to claim 4, wherein R², R³ and R⁴ each represents amethyl group; R² represents a methyl group, and R³ and R⁴ are takentogether to represent an ethylene group; R² and R³ each represents amethyl group, and R⁴ represents a phenyl group; or R² and R³ eachrepresents a methyl group, and R⁴ represents a 3,4-methylenedioxyphenylgroup.
 6. The compound according to claim 2, which is (1)1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylamine, or (2)1-(2-(α,α-dimethylbenzyl)-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropylamine.7. The compound according to claim 3, which is (1) t-butylN-(1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)carbamate,or (2) t-butylN-(1-(2-(α,α-dimethylbenzyl)-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)carbamate.8. A process for producing a compound represented by formula (I-2):

(wherein symbols in the formula have the same meanings as describedbelow), comprising reacting a compound represented by formula (V):

(wherein R⁵ has the same meaning as in claim 3) with a compoundrepresented by formula (VI):

(wherein R², R³, and R⁴ have the same meanings as in claim 1).
 9. Aprocess for producing a compound represented by formula (I-1)

(wherein symbols in the formula have the same meanings as describedbelow), comprising subjecting a compound represented by formula (I-2):

(wherein R², R³, R⁴ and R⁵ have the same meanings as in claim 3) to adeprotection reaction of the amino-protecting group.
 10. A process forproducing a compound represented by formula (III):

(wherein R², R³, R⁴ and R⁶ have the same meanings as described below)comprising subjecting a compound represented by formula (I-2):

(wherein R², R³, R⁴, and R⁵ have the same meanings as described in claim3) to a deprotection reaction of the amino-protecting group, andsubjecting the resulting compound represented by formula (I-1):

(wherein symbols in the formula have the same meanings as describedabove) to an amidation with a compound represented by formula (IV):

(wherein R⁶ represents an amino-protecting group).
 11. A process forproducing a compound represented by formula (II):

(wherein symbols in the formula have the same meanings as describedbelow), comprising subjecting a compound represented by formula (I-2):

(wherein R², R³, R⁴, and R⁵ have the same meanings as in claim 3) to adeprotection reaction of the amino-protecting group, reacting theresulting compound represented by formula (I-1):

(wherein symbols in the formula have the same meanings as describedabove) with a compound represented by formula (IV), and subjecting theresulting compound represented by formula (III):

(wherein R², R³, R⁴ ₁ and R⁶ have the same meanings as in claim 10) to adeprotection reaction of the amino-protecting group.